Since the class I molecules are self antigens present on the surface of all cells in the body, the immune system must be rendered tolerant to them. Yet, these class I antigens must be recognized by cytotoxic T-cells in the associative recognition of virus-infected and tumor cells. In our analysis of class I genes, we have identified a related gene which may function to regulate this self-nonself recognition. This class I gene is expressed only in the liver and encodes a secreted class I antigen. Our demonstration of the secretion of a class I antigen by the liver has explained a previous observation that liver grafts across histocompatibility barriers were never rejected and has led us to suggest that this molecule serves to modulate class I restriction. We reasoned that a molecule with class I specificity that is constantly secreted into the circulation could act as a "blocking" factor, leading to suppression of class I recognition. The level of expression of such a blocking factor may act directly to modulate self-nonself recognition that will destroy aberrant cell types but not normal cells. This hypothesis has significant implications and suggests a means to modulate the host's response to neoplastic and autoimmune diseases. Attempts are being made to determine what regulates the expression of this particular class I gene.